Research Papers:

Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer

Chi-Yuan Chen _, Chia-Ing Jan, Wen-Chieh Pi, Wen-Lung Wang, Pan-Chyr Yang, Tong-Hong Wang, Rotem Karni and Tzu-Chien V. Wang

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Oncotarget. 2016; 7:16760-16772. https://doi.org/10.18632/oncotarget.7606

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Chi-Yuan Chen1, Chia-Ing Jan2,3, Wen-Chieh Pi4, Wen-Lung Wang5, Pan-Chyr Yang6, Tong-Hong Wang1,7, Rotem Karni8, Tzu-Chien V. Wang4

1Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan 333, Taiwan

2Department of Pathology, China Medical University and Hospital, Taichung, Taiwan 404, Taiwan

3Department of Pathology, China Medical University and Beigang Hospital, Yunlin, Taiwan 651, Taiwan

4Department of Molecular and Cellular Biology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan

5Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 833, Taiwan

6Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan

7Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 333, Taiwan

8The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel

Correspondence to:

Tzu-Chien V. Wang, e-mail: tcvwg@mail.cgu.edu.tw

Keywords: hnRNP A1, hnRNP A2, Tid1, EGFR, NSCLC

Received: September 18, 2015    Accepted: February 10, 2016    Published: February 23, 2016


The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis.

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